In most aseptic pharmaceutical cleanrooms, the final step in removing airborne particles occurs in a high efficiency particulate air (HEPA) or ultra-low penetration air (ULPA) filter that is delivering air into a controlled space. Whether the cleanroom attains and maintains its designed cleanliness class depends largely on the performance of these filters. Hence, it is a common and good practice to test the performance of all filters installed in cleanrooms to ensure that they meet the designed specifications. Filters are typically tested at the time of manufacture for overall efficiency and leaks. However, in some cleanrooms within regulated industries, such as the pharmaceutical industry, these filters are also required to be certified periodically to ensure acceptable performance during their service life. Various organizations issue recommended practices for certification of HEPA and ULPA type filters for filter leak tests and guidelines for testing and classifying such filters.
In current HEPA air filtration micro-glass media, the standard utilized in the pharmaceutical industry in aseptic processing has serious problems due to the media being fragile resulting in damage from handling, pressure, overloading and the like. Such damage can result in leaks of the filtration media thereby compromising functionality. Leakage and damage of microglass filtration media within the pharmaceutical cleanroom environment is significant such that the U.S. Food and Drug Administration has issued guidelines ensuring filtration effectiveness of microglass HEPA filters by testing on a regular basis. Testing of such microglass HEPA filters in such aseptic environment is completed using high concentration oil based aerosols such as DOP (dioctylphthlate), PAO (poly-alpha olefin), DEHS (Di-Ethyl-Hexyl-Sebacat), and other similar compounds measured by traditional photometers capable of measuring such upstream and downstream concentrations. The aerosols used for such filter leak tests and challenging of these filters should meet specifications for critical physicochemical attributes such as viscosity. Leakage threshold rates of 0.01% or greater of upstream concentration from these compounds is typically the testing limit at which the pharmaceutical installation and processing area would either have to replace the filter or repair the same. The upstream concentration typically is measured at the start and end of testing to ensure that the upstream challenge remains consistent over the life of the test. The filter face is scanned to identify defects in the filter media.
Since the 1960's HEPA filters have been tested using high concentrations (e.g., approximately 20 μg/liter) of aerosols such as PAO, DOP, DEHS, and other similar compounds. Traditionally, HEPA filters are tested with photometers which require a high (>10 μg/liter) upstream challenge concentration. Considering a leak size of 0.01% of the upstream concentration, this means that on the downstream side of the filter one must be able to detect a very small amount of PAO. The photometer has a lower limit of being able to measure small concentrations, which is why the larger upstream concentrations are required. A particle counter is another piece of equipment that can be used to leak test filters. Particle counters, unlike photometers, are only able to work with very low concentrations of PAO and are much more sensitive at very or ultra low concentrations of aerosol.
High concentrations of oil have a much greater impact on ePTFE than on glass media HEPA filters. Studies have shown that testing glass media HEPA filters with a photometer at high concentrations (e.g., approximately 20 μg/l) and with a particle counter at low concentrations (e.g., approximately 0.1 μg/l) yield consistent results in regards to sizing leaks. Therefore, there is a desire to develop test apparatus and methods for testing filters (especially, but not limited to, ePTFE HEPA filters) at low concentrations.
In general, however, there has not been a very convenient way to steadily produce a very low concentration of PAO. In the past a Laskin nozzle generator was used and the output was dumped into filters, or other output reduction methods were used. None of these have been ideal, however. The output of typical Laskin nozzle-based aerosol generators is governed by the amount of air flow exiting the nozzle tip. A standard Laskin nozzle requires approximately 2.65 cfm @ 20 psi of compressed air to enter the nozzle, thus resulting in 2.65 cfm of the aerosol mixture that will exit the generator. Air flow through the nozzle equates to flow combined with oil droplets out of the generator. In certain applications, the aerosol output of a generator operating on one Laskin nozzle will result in output concentrations with orders of magnitude higher than desired.
One possible solution to generating lower concentrations is to use a fraction of the Laskin nozzle output under the surface of the oil. Another possibility is to reduce the nozzle pressure. It is common practice to reduce the air pressure to a standard Laskin nozzle or to modify the nozzle by plugging one or more of the holes in the nozzle to reduce the overall aerosol output of the generator. The problem with using a smaller nozzle and/or lower nozzle pressures is that very little air passes through the nozzle and out of the tank. Another problem is that some specialized filter housings may require higher air flow. For example, some filter housings with aerosol injection/dispersion features are typically used with >2 cfm of airflow to inject the aerosol across the filter face. If very low flow were used, the aerosol may be difficult to be injected across the filter face in one of these units. Additionally, the time required for newly generated aerosol to exit the holding tank increases as nozzle flow decreases. This creates a slow response time in generator output at first startup or when attempting to change the nozzle pressure/generation rate of the generator. This increased exit time of the aerosol can also lead to an increase in aerosol particle size with time. A newly generated aerosol that is composed of small particles has a higher probability to grow in size by means of coalescence, ripening, agglomeration, etc., the longer it remains in a high aerosol concentration environment.
The DOP/PAO method for aseptic pharmaceutical room filtration application discussed above is required by regulation at least every 6-12 months by challenging the filtration media with a defined aerosol. The required aerosol challenge is maintained at a high concentration of about 20 μg PAO/L of air. A measurement of 15 μg of PAO/liter corresponds to about 20 grams of PAO/800 cfm filter/hour. For normal or standard microglass filtration media, a one-time oil based challenge compound may not negatively impact filter life of the media but may affect other structures of the filter. However, by testing at such concentrations on a regular basis, standard filter life including regular challenge testing can limit to less than five years the life cycle for microglass HEPA filtration.
In such standard challenging methodology for pharmaceutical applications and installs, a predefined challenging compound such as PAO is provided upstream of the filtration media in place. The PAO is injected into the airstream upstream of the in-situ media by nozzle or other known device at high concentration levels to properly determine filtration effectiveness. Injection devices such as a Laskin Nozzle create a poly-dispersed aerosol composed of particles with light scattering mean droplet diameters in the submicron size range. A challenge concentration, as mentioned, is provided up to about 20 μg/L which is continually introduced upstream of the filter for about three to four hours for a typical certification. An upstream challenging port in the filter housing is utilized for photometric analysis. The filter face is scanned on the downstream side with the photometer probe and leak sizes are calculated as a percent of the upstream challenge. Scanning is conducted on the entire face of the filter to generate proper leakage analysis. Probe readings of about 0.01% as leak criteria would be indicative of a significant leak but requires, as seen, fairly high concentrations of upstream PAO which can have deleterious effects on the filtering media and HEPA performance.
Significant problems also arise in the use of PAO challenge compounds. Significant fouling of the filtration media may occur over a plurality of challenging cycles. Further, such excessive challenging can cause the filter media to become less efficient, exhibiting more of a pressure drop and correspondent higher energy costs. Additionally, the PAO challenge compound has been shown to potentially cause damage to the filtering gel seals and gaskets resulting in potential leakage points. PAO may further cause liquification of silicon based gels or may harden or otherwise reduce the effectiveness of urethane based gel seals.
As a result, improved aerosol generators are required which can effectively produce aerosols of lower concentrations of appropriate challenge compounds to a filtration media, but which can do so consistently for the required amounts of time, and without causing excessive oiling or buildup on the filtration media, and without creating excessive pressure drop across the media.
Filter housings containing PAO dispersion manifolds can be used to provide a uniform aerosol distribution upstream of a filter when performing filter tests. These dispersion manifolds are designed to typically operate properly with a minimum of 2.65 cfm of air. When reducing the pressure below 20 psi for a full Laskin nozzle, or plugging a fraction of the nozzle holes, the output of the generator can fall below the optimal flow to effectively operate the dispersion manifolds. To compensate for the reduction of airflow through the generator outlet, one option is to increase the total output of the generator by adding additional supply air at the generator output. Under this operation, the newly formed aerosol exits the generator before combining with the additional supply air and the transit time for the aerosol to exit out of the holding tank is largely unaffected. However, if supply air is added at the generator output, there can be problems with the supply air not mixing properly with the generated aerosol.
Alternative aseptic pharmaceutical filter designs have included the use of additional pre-filter requirements which work to protect the primary filtration media during normal air handling load and during challenging. Prefilters typically are designed to prevent surface loading due to large particles, such as hair, etc. Such pre-filters, however, can foul earlier in the filter life cycle thereby requiring periodic replacement and increased maintenance costs. Such pre-filtering is undesirable in that additional filtration media is therefore required, doubling of maintenance and handling requirements are expected and a lack of efficiency and increased pressure drop result.
Other problems associated with traditional micro-fiberglass HEPA filters are that they are a relatively fragile filter medium which do not react well to handling, in-place contact, vibration, humidity possibly condensing on the filter media or the particle board frames, or chemical exposure. Such micro-fiberglass media may be readily damaged through normal handling. Damage resulting from these various factors can cause leakage and unfiltered air to pass through the media. Further, the filter can fail normal challenging sequences as a result of such damage to the media. Thus, it is desirable to provide a filtering media that meets full HEPA filtration requirements, may be utilized in the aseptic pharmaceutical industry environment, and is more durable for handling and more reliable in remaining fully functional after required integrity tests or challenging sequences and during normal course of operations.
In addition to filter loading, when considering testing of filters with the conventional use of PAO as a challenge aerosol, under certain conditions, bleed through can also be a potential issue. The issue of bleed through may occur when operating a thermal PAO generator at lower pressures to test ePTFE or glass media filters. This is due to the thermally generated aerosol having a 0.10-0.45 mass mean diameter which is closer to the MPPS of the filter. This creates an issue with a photometer measuring a concentration and looking for leaks at or above 0.01%. The bleed through could erroneously manifest itself as an artificially large leak or in some cases a continuous leak across the filter measuring >0.01%.
It is therefore desirable to provide a fully functional HEPA filtration media which meets all requirements, is relatively durable, may be challenged appropriately to determine filtering effectiveness and leakage and which further meets all required aseptic filtration standards. It is further desirable to provide such filtration media without additional pre-filter requirements and with appropriate methodology to determine full functionality of the media and determine possible leakage points without causing fouling of the in-situ filters.
It is also desirable to provide an aerosol generator capable of producing a steady, consistent output of low concentration challenge compound so as to be compatible with the use of discrete particle counters used for leak testing filter media.
Thus, there is a need in the art to provide a fully functional aseptic pharmaceutical filter media which has associated full testing methodology, is durable, maintains HEPA filtration efficiencies and which has a long in-place filtration life.